The present invention is concerned with a novel process for the preparation of thiazolidinedione derivatives, especially with the preparation of 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione and its salts. 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione and its salts are pharmaceutically active compounds. These compounds are known in the art and are described for example in International Patent Application WO 94/27995. They are especially useful for the prophylaxis and/or treatment of diabetes mellitus type I and II.
Methods for the preparation of 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione have been described in WO 94/27995. However, these methods include a large number of individual reaction steps. Further, the methods known in the art exhibit a low yield, which makes them unsuitable for the commercial large scale production of 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione.
It has surprisingly been found that using the process according to the present invention 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione can be prepared with less process steps under moderate conditions with an outstanding yield.
The present invention refers to a process for the preparation of compounds of formula I 
comprising bromomethylation or chloromethylation of a compound of formula II 
to obtain a compound of formula III 
and subsequent reaction with a compound of formula IV 
to yield said compounds of formula I,
wherein R1 represents aryl or heteroaryl and X represents Cl or Br.
This process provides an efficient method for producing compounds of formula I. Compared to the processes known in the art, the process of the present invention exhibits a higher yield as well as a reduced number of reaction steps. Further, crude intermediate products can mostly be used in subsequent reaction steps without the need of any additional purification steps.
According to the present invention, terms xe2x80x9cchloromethylationxe2x80x9d and xe2x80x9cbromomethylationxe2x80x9d signify the introduction of a xe2x80x94CH2Cl or xe2x80x94CH2Br group respectively.
The term xe2x80x9cmesylationxe2x80x9d signifies the introduction of a methanesulfonyl group which can e.g. be performed by a reaction with methanesulfonylchloride.
The term xe2x80x9ctosylationxe2x80x9d signifies the introduction of a toluenesulfonyl group which can e.g. be performed by a reaction with toluenesulfonylchloride.
In this specification the term xe2x80x9clowerxe2x80x9d is used to mean a group consisting of one to seven, preferably of one to four carbon atom(s).
The term xe2x80x9calkylxe2x80x9d refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms.
The term xe2x80x9clower alkylxe2x80x9d refers to a branched or straight chain monovalent alkyl radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, i-butyl, n-butyl, t-butyl and the like with methyl and ethyl being preferred.
The term xe2x80x9calkoxyxe2x80x9d refers to the group alkyl-Oxe2x80x94, the term xe2x80x9clower alkoxyxe2x80x9d to the group lower-alkyl-Oxe2x80x94.
The term xe2x80x9carylxe2x80x9d relates to the phenyl or naphthyl group which can optionally be mono-, di- or tri-substituted by alkyl, halogen, hydroxy, alkoxy, aryloxy, or aryl-alkoxy. Mono- and di-substituted phenyl or naphthyl groups are preferred.
The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic 5- or 6-membered ring which can contain 1 or 2 atoms selected from nitrogen, oxygen or sulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thiophenyl, isoxazolyl, oxazolyl or imidazolyl. A heteroaryl group may have a substitution pattern as described earlier in connection with the term xe2x80x9carylxe2x80x9d.
The term xe2x80x9chalogenxe2x80x9d refers to fluorine, chlorine, and bromine, preferably to chlorine and bromine and more preferably to bromine.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to conventionally known pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, D-tartaric, L-tartaric, malonic, methane sulfonic and the like. In addition, certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counter-ion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases. The pharmaceutically acceptable salts are formed by taking about 1 equivalent of a compound of Formula I and contacting it with about 1 equivalent of the appropriate corresponding acid of the salt which is desired. Work-up and isolation of the resulting salt is well-known to those of ordinary skill in the art.
In detail, the present invention refers to a process for the preparation of compounds of formula I 
comprising bromomethylation or chloromethylation of a compound of formula II 
to obtain a compound of formula III 
and subsequent reaction with a compound of formula IV 
to yield said compounds of formula I,
wherein R1 represents aryl or heteroaryl and X represents Cl or Br.
In a preferred embodiment of the invention, a compound of formula II is bromomethylated. In a more preferred embodiment said bromomethylation is carried out in a solvent in the presence of HBr and formaldehyde.
Solvents for the above reaction are known to persons skilled in the art. Preferred solvents are aromatic solvents, e.g. toluene, halogenated hydrocarbons, e.g. CH2Cl2, esters, e.g. ethylacetate, ethers, e.g. dioxane, and mixtures thereof. A particularly preferred solvent is CH2Cl2.
Formaldehyde can be provided as formaline solution, trioxane or paraformaldehyde. Preferrably formaldehyde is provided as trioxane in said bromomethylation.
HBr can be provided as gas or as aqueous solution. Aqueous solutions are commercially available, e.g. at concentrations of 48% or 62%. The bromomethylation can e.g. be carried out with aqueous HBr of a concentration between 30% and 69%. An aqueous solution with a HBr concentration in the range between 45% and 62% is preferred.
The bromomethylation can be carried out in a wide range of temperatures, e.g. from xe2x88x9220 to +40xc2x0 C. Preferably, the bromomethylation is carried out at a temperature between xe2x88x9210 and +10xc2x0 C. The atmospheric pressure during the reaction is not critical.
The reaction of a compound of formula III with a compound of formula IV may proceed by the formation of a salt of a compound of formula IV, e.g. a di-sodium salt, a di-potassium salt or a di-lithium salt, followed by reaction of that salt with the compound of formula III. A di-potassium salt of a compound of formula IV can be prepared by methods known in the art, e.g. by reacting a compound of formula IV with potassium amide in liquid ammonia or with potassium tert.-butoxyde in THF. Methods for preparing a di-sodium salt of a compound of formula IV are also known in the art, e.g. by reacting a compound of formula IV with sodium amide in liquid ammonia or with sodium tert.-butoxyde in THF.
A further preferred embodiment relates to a process as described before, wherein said reaction of a compound of formula III with a compound of formula IV comprises the formation of a di-lithium salt of a compound of formula IV. Said di-lithium salt can e.g. be obtained by reacting a compound of formula IV with lithium diisopropylamide in THF.
Preferably R1 represents phenyl. In another preferred embodiment R1 represents thiophen-2-yl.
If desired, compounds of formula I can be converted to a corresponding salt, preferably a pharmaceutically acceptable salt, most preferably the sodium salt. Such a conversion may be carried out under basic conditions, preferably with NaOH in THF. One embodiment of the above described process comprises the conversion of a compound of formula I to the corresponding sodium salt.
Scheme 1 summarizes one possible embodiment of the above described process and the reaction conditions for the individual reaction steps. 
The reaction conditions for the above reaction can vary to a certain extent. Methods to perform the above described reactions and processes are known in the art or can be deduced in analogy from the examples.
The present invention also relates to processes for the preparation of starting materials for the preparation of compounds of formula I. Accordingly, the present invention relates to a process for the preparation of compounds of formula V 
comprising bromination, preferably in xcex3-position, of a compound of formula VI, 
condensation of the resulting compound with an amide R1C(O)NH2 to obtain a compound of formula VII, 
reduction of the compound of formula VII and subsequent introduction of a xe2x80x94SO2R2 group to yield said compounds of formula V, wherein
R1 represents aryl or heteroaryl,
R2 represents lower alkyl, aryl or trifluoromethyl, and
R3 represents lower alkyl.
Another embodiment of the present invention relates to a process for the preparation of compounds of formula V 
comprising converting a compound of formula VI 
to a compound of formula VIII, 
and bromination, preferably in xcex3-position, of a compound of formula VIII to yield a compound of formula X, 
or, alternatively comprising bromination, preferably in xcex3-position, of a compound of formula VI and subsequent transformation to a compound of formula X,
and subsequent condensation of the compound of formula X with an amide R1C(O)NH2 to obtain a compound of formula VII, 
reduction of the compound of formula VII and subsequent introduction of a xe2x80x94SO2R2 group to yield said compound of formula V, wherein
R1 represents aryl or heteroaryl,
R2 represents lower alkyl, aryl or trifluormethyl,
R3 represents lower alkyl,
R4 represents lower alkyl, lower-alkyl-carbonyl, lower-alkoxy-carbonyl, aryl-carbonyl, P(O)(OR5)2, or Si(R6)3,
each R5 independently represents lower alkyl or aryl, and
each R6 independently represents lower alkyl or aryl.
A preferred embodiment of the invention relates to processes wherein R4 represents methyl, ethyl, acetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, diethylphosphate, trimethylsilyl, triethylsilyl, or triphenylsilyl, with methyl being preferred. If R4 represents P(O)(OR5)2 or Si(R6)3 the individual R5 or R6 substituents respectively may be different such as in ethylmethylphosphate or as in dimethylethylsilyl.
In a preferred embodiment the invention relates to processes as described above, in which R2 is methyl, ethyl, trifluoromethyl, or 4-methyl-phenyl, with methyl being more preferred. Preferably, R3 signifies methyl or ethyl. Preferably, R1 represents phenyl and in another preferred embodiment R1 represents thiophen-2-yl.
The introduction of a xe2x80x94SO2R2 group can e.g. be a mesylation or a tosylation.
Methods for preparing compounds of formula VIII from compounds of formula VI are known in the art, e.g. reacting a compound of formula VI with a suitable orthoformat as described in the examples or by analogous methods. See Patwardhan, et al., Synthesis 1974, 348.
In cases where R4 represents lower-alkyl-carbonyl, lower-alkoxy-carbonyl, aryl-carbonyl, P(O)(OR5)2, or Si(R6)3 it may be more convenient, to carry out first the bromination, preferably in xcex3-position, of a compound of formula VI and then introducing the group R4 prior to the subsequent condensation with an amide R1C(O)NH2. Methods for performing such reactions are described in the examples or can be deduced in analogy to the examples. Further, brominated compounds of formula VI can be reacted e.g. with:
suitable chloroformates,
suitable phosphoric acid ester chlorides,
suitable silyl chlorides
to introduce the desired group R4.
The bromination of a compound of formula VI can be carried out by methods known in the art, e.g. by reacting a compound of formula VI with bromine in the presence of p-toluenesulfonic acid monohydrate in dichloromethane.
The bromination of a compound of formula VIII can be carried out by methods known in the art, e.g. by reacting a compound of formula VIII with N-bromo-succinimide in the presence of 2,2xe2x80x2-azobis(2-methylpropionitrile) in carbon tetrachloride.
Condensation of brominated compounds of formula VI or VIII with an amide R1C(O)NH2 can be carried out by methods known in the art, e.g. by methods described in the examples or by analogous methods.
Scheme 2 summarises one possible embodiment of the above described processes and the reaction conditions for the individual reaction steps. 
The reaction conditions for the above reaction can vary to a certain extent. Methods to perform the above described reactions and processes are known in the art or can be deduced in analogy from the examples.
Compounds of formula II can be obtained by methods known in the art, as e.g. described in WO 94/27995. One possibility to obtain compounds of formula II is by reacting compounds of formula V with compounds of formula IX 
under basic conditions. The reaction may be performed in solvents like DMF or THF with for example sodium carbonate, potassium carbonate, sodium t-butylate, or potassium t-butylate or by phase transfer methods. Methods for the preparation of compounds of formula IX are known in the art, e.g. from Iwasaki et al., J. Org. Chem. 1991, 56, 1922.
A further embodiment of the invention comprises a process according to any of the above described processes for the preparation of 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione or Sodium 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedionate comprising
a) reacting methyl 3-oxovalerate (commercially available) with bromine to give methyl 4-bromo-3-oxovalerate, or reacting ethyl 3-oxovalerate (commercially available) with bromine to give ethyl 4-bromo-3-oxovalerate,
b) reacting methyl 4-bromo-3-oxovalerate with benzamide to give methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate, or reacting ethyl 4-bromo-3-oxovalerate with benzamide to give ethyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate,
c) converting methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate to 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol, or converting ethyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate to 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol,
d) reacting 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol with methanesulfonylchloride to give 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol methansulfonyl ester,
e) reacting 2-(5-Methyl-2-phenyl-4-oxazolyl)ethanol methanesulfonyl ester with 4-hydroxybenzothiophene (see Napier, et al., J. Heterocycl. Chem. 1970, 7, 393 for source) to give 4-[2-(benzo[b]thiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole,
f) reacting 4-[2-(benzo[b]thiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole with formaldehyde and HBr to give 4-[2-(7-Bromomethyl-benzo[b]thiophen-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole,
g) reacting 4-[2-(7-Bromomethyl-benzo[b]thiophen-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole with 2,4-thiazolidinedione (commercially available) to give 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione,
h) optionally converting 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione to Sodium 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedionate.
A further embodiment of the invention comprises a process according to any of the above described processes for the preparation of 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione or Sodium 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedionate comprising
a) reacting methyl 3-oxovalerate with methyl orthoformate (commercially available) to give methyl (E)-3-methoxy-2-pentenoate,
b) brominating methyl (E)-3-methoxy-2-pentenoate to form methyl (E)-4-bromo-3-methoxy-pent-2-enoate,
c) reacting methyl (E)-4-bromo-3-methoxy-pent-2-enoate with benzamide to give methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate,
d) reducing methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate to 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol,
e) reacting 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol with methanesulfonylchloride to give 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol methansulfonyl ester,
f) reacting 2-(5-Methyl-2-phenyl-4-oxazolyl)ethanol methanesulfonyl ester with 4-hydroxybenzothiophene to give 4-[2-(benzo[b]thiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole,
g) reacting 4-[2-(benzo[b]thiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole with formaldehyde and HBr to give 4-[2-(7-Bromomethyl-benzo[b]thiophen-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole,
h) reacting 4-[2-(7-Bromomethyl-benzo[b]thiophen-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole with 2,4-thiazolidinedione to give 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione,
i) optionally converting 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione to Sodium 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedionate.
The invention further comprises the use of any of the above described processes for the preparation of 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}-2,4-thiazolidinedione and of 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}-2,4-thiazolidinedione -Na-salt.
A further embodiment of the present invention comprises compounds of formula III 
wherein R1 represents aryl or heteroaryl and X represents Cl or Br. Compounds of formula III wherein X represents Br are preferred. Compounds of formula III wherein R1 represents phenyl or wherein R1 represents thiophen-2-yl are also preferred. Methods for the preparation of compounds of formula III are described above and are further elucidated by the examples.
The invention further relates to compounds of formula X 
wherein
Y represents Cl or Br,
R3 and R4 have the significances given above
with the provisio that R4 may not be methyl if Y is Br and/or R3 is methyl.
Methods for preparing compounds of formula X are described above and are further elucidated by the examples. It is e.g. possible to introduce the substituent Y=Cl in analogy to the introduction of Y=Br by means of a reaction with N-chloro-succinimide.